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TET1 is an important transcriptional activator of TNF expression in macrophages

Sun, F;Abreu-Rodriguez, I;Ye, S;Gay, S;Distler, O;Neidhart, M;Karouzakis, E;

Activation of macrophages and overexpression of TNF is associated with the pathogenesis of chronic inflammatory diseases. However, the mechanisms leading to TNF overexpression are still unknown. 5-methylocytosine (5-mC) is an epigenetic modification that is associated with silenced genes. Recent studies showed that it is converted to 5-hydroxylmethylocytosine (5-hmC) and reactivates gene expression through the action of the family of Ten-Eleven-Translocation (TET1-3) enzymes. In this study, we show that 5-hmC levels are increased globally and specifically in the TNF promoter during the differentiation of monocytes to macrophages. In addition, the levels of 5-hmC are increased upon LPS stimulation of macrophages. Furthermore, CRIPSR stable knockout of TET1 decreases the expression of TNF and other pro-inflammatory cytokines. In conclusion, we showed that TET1 contributes to the activation of macrophages possibly through regulation of 5-hydroxymethylation in the promoter of pro-inflammatory cytokine genes. The TET1 enzyme could be a promising therapeutic target to inhibit the persistent inflammation caused by macrophages in chronic inflammatory diseases.

  • PubMed ID: 31216336